An In Silico Analysis of Genetic Variants and Structural Modeling of the Human Frataxin Protein in Friedreich’s Ataxia

Da Conceição, L.M.A.; Cabral, L.M.; Pereira, G.R.C.; De Mesquita, J.F. An In Silico Analysis of Genetic Variants and Structural Modeling of the Human Frataxin Protein in Friedreich’s Ataxia. Int. J. Mol. Sci. 2024, 25, 5796. doi:10.3390/ijms25115796 

Overall, 226 missense mutations in human frataxin were compiled from the literature and databases, which underwent a thoroughly functional characterization in silico. This study also provided an unprecedented, complete, and accurate three-dimensional model of human frataxin, serving as a basis for constructing the structure of clinically relevant variants, I154F and W155R. Our MD findings suggest that these mutations disturb FXN’s inherent structure and dynamics, primarily within the N-terminal domain. This behavior could compromise the protein’s ability to adopt functional conformations, potentially leading to impaired recognition and cleavage by the MPP protein, which is directly involved in FXN maturation, as outlined in previous studies. Thus, our findings provide valuable insights into the molecular basis of FXN dysfunction in FRDA, shedding light on future directions that could be explored for developing new therapeutic strategies.